Creatine

Introduction:

Creatine is available in nutrition stores throughout the country in the form of creatine monohydrate. It has been used as an investigational agent in the form of IV creatine phosphate. Natural creatine is a substance produced in the liver and obtained from food sources that helps supply energy to cells all over the body – particularly muscle cells which have high energy demands. Because of creatine’s ability to supply energy where it is demanded, the supplement form is mainly used by athletes to increase their ability to produce energy rapidly, improving athletic performance and allowing them to train harder. However, creatine is not only used by athletes to improve athletic ability, it may also improve cognition or help in the treatment of neuromuscular and neurodegenerative disorders such as Parkinson’s disease and congestive heart failure. Within this writeup, unless specified elsewhere creatine refers to creatine monohydrate oral supplement.

 

Creatine dosage:

The dose of creatine used has been variable in research. The most common dosage taken has been creatine monohydrate at an oral dose of 20 grams per day in 4 divided doses for 5 days followed by a maintenance dose of 5 grams per day up to 12 weeks (3). The highest dose noted in research was 20 grams by mouth daily for 8 weeks (3), and the longest duration of creatine dosing was 4 grams per day by mouth for 2 years (17).

 

Creatine and enhancement of athletic performance:

Creatine, lean body mass, strength, endurance, and power:

Leg strength, endurance, average power, and lean muscle increased in older men (average age, 70.4 years) after taking creatine (Cr) supplementation of 0.3 grams per kilogram of body weight for the first 5 days and then 0.07 per kilogram of body weight. Compared to placebo, participants taking Cr experienced significantly greater increases in lean mass (3.3 kg vs 1.3 kg), higher leg press weight (50.1 kg vs 31.3kg), knee extension endurance (21 reps vs 14 reps), and average power output (26.7 watts vs 18 watts). (1)

 

Creatine and sprints by men vs. women:

Creatine (Cr) supplementation (0.35 g/kg of fat-free mass) for 3 days significantly increased body mass (+0.9 kg), thigh muscle volume (+6.6%) and sprint performance (total work during the first sprint and peak power during sprints 2 to 6) in this study that included 20 athletes (50% male). Enhanced performance was greater for men than women during the first sprint but in later sprints women experienced a greater effect. (2)

 

Creatine, strength, and power:

The researchers reviewed 16 creatine and weight lifting studies into one analysis of creatine’s effect on strength and power in healthy adults. The maximum lifted weight difference between the placebo group and the creatine groups differed by 6.85 kg. The creatine group was also able to bench press 9.76 kg more than the placebo group. However, there was no difference in cycle ergometer or isokinetic dynamometer performance. The creatine group was able to lift more weight than the placebo group in every study. The evidence of using creatine supplementation with resistance training showed improved performance in young men, however they could not find enough evidence for improved performance in older individuals or women or for other types strength and power exercises, and further study is needed for these groups. This review did not include the 2 prior studies mentioned above which showed strength improvements in both older men and women respectively. (3)

 

Creatine and endurance sports:

While creatine may enhance the performance of high-intensity, short-duration exercise, it is not useful in endurance sports (4).

 

Creatine and older adults:

A review of the literature on creatine supplementation in adults aged 55-82 years suggested that creatine safely promotes better muscle strength and hypertrophy than resistance training alone. Creatine supplementation should therefore be strongly considered as a safe, inexpensive and effective nutritional intervention to help slow the rate of muscle deterioration with age, particularly when consumed in conjunction with a resistance training regimen. (5)

 

Creatine monohydrate plus whey protein for resistance training:

Research suggests that combining whey and creatine may offer benefits for enhancing the effects of resistance training. Thirty-six men were randomly assigned to supplementation with whey protein (1.2 g/kg/day), whey protein and creatine monohydrate (0.1 g/kg/day), or placebo (1.2 g/kg/day maltodextrin) for 6 weeks. Results indicated that men who supplemented with whey and creatine demonstrated greater gains in lean tissue mass and bench press strength, compared with men who supplemented with whey alone or with placebo. The group taking whey protein without creatine also showed better strength gains than the placebo group. (6)

 

Creatine monohydrate and bone health:

Creatine and bone density: Researchers suggest that creatine (Cr) may increase bone density by improving muscle size and strength. For 12 weeks, participants (n=29 men, aged 71 years) were randomized to received creatine (0.3 g/kg creatine for 5 days and then 0.07 g/kg) or placebo in addition to resistance training. Bone mineral content and density were measured using dual energy X-ray absorptiometry before and after training.  Results showed a 0.5% and 1% increase in whole-body and leg bone density, respectively. Arms bone mineral contents increased significantly in the Cr group by 3.2 % (vs a non-significant increase of 1.0% with placebo). (7)

 

Creatine monohydrate and patients on dialysis:

Use of creatine monohydrate, supplement used to increase muscle, for the treatment of muscle cramping due to hemodialysis was examined in 10 patients who were randomized to receive 12 mg creatine monohydrate or placebo before each dialysis session for 4 weeks. After creatine monohydrate administration, creatine levels increased by 1.7 mg/dL. In the creatine monohydrate group, results showed a 60% reduction the frequency of muscle cramps, which later disappeared when creatine monohydrate treatment was stopped. No benefit was reported in the placebo group. No serious side-effects were reported. (9)

 

Creatine and chronic heart failure:

Muscle endurance improved in a double-blind, placebo-controlled crossover study of patients with chronic heart failure. Treatment with 20 g of creatine for 5 days increased the amount of exercise they could complete before they reached exhaustion. No effect was reported in the placebo group. Chemicals produced during exhaustive exercise (ammonia and lactate) were reduced (-2.7 and -0.05 micromols per liter per contraction, respectively) with use of creatine but not with placebo. (10)

 

Creatine phosphate and coronary artery bypass surgery:

The use of creatine phosphate in individuals undergoing coronary artery (heart) surgery was examined in 50 patients who were administered either creatine phosphate or placebo during surgery. Findings show a reduction in arrhythmia rates and lower CK and CKMB level in patients during and after surgery when creatine phosphate was administered without significant difference in blood pressure and heart rate monitoring including patients with worse ventricular systolic function than in controls. (11)

Creatine phosphate and coronary artery bypass surgery: Creatine phosphate (CP) administered to patients before undergoing coronary artery surgery had beneficial effects on the heart. Patients received either CP (n=20)  or standard caridoplegic solution (control group, n=20). Three days before surgery, those in the CP group received 6 grams of CP daily in two 20-min IV sessions. During surgery, standard cardioplegic solution enriched in CP (10 mmol/l) was given. After surgery 4.0 g/day of CP was administered in 2 IV injections for 2 days. Results show improved heart function after bypass surgery in patients administered CP. Ventricular arrhythmias (abnormal rapid heart rhythms) during and after surgery improved with CP. CP treatment also significantly reduced use of inotropic drugs (used to strength the heart) and damage seen in the heart muscle. (12)

 

Creatine use in older Parkinson’s patients:

Creatine appears to be safe for older individuals, according to study by Bender et al. The investigators assessed the long-term effects of creatine supplementation on 60 elderly individuals with Parkinson’s disease. The participants took a dose of 4 g/d of creatine daily for 2 years without major side effects. The most commonly reported side effect resulting from creatine supplementation was gastrointestinal distress and there was no indication of altered kidney function. Overall, creatine was well tolerated in older age patients. (17)

 

Creatine and cognition in older patients:

A study of 32 older people revealed that creatine supplementation aids cognition in the elderly. Participants were divided into two groups, Group 1 (n = 15) were given 5 g four times a day of placebo for 1 week, followed by the same dosage of creatine for the second week and group 2 (n = 17) were given placebo both weeks. All participants were tested on random number generation, forward and backward number and spatial recall, and long-term memory tasks to establish a baseline level. Participants were retested at the end of each week. Findings showed a significant positive effect of creatine supplementation on all tasks except backward number recall. (18)

 

Creatine adverse reactions and interactions:

Creatine adverse reactions: Most research on use of creatine documented that this supplement is safe, and tolerated well with minimal side effects. Creatine should only be considered under a physician’s direction if kidney function will be evaluated prior to taking creatine and patients should be advised to report major reactions during use. Reports have linked creatine to weight gain, cramping, dehydration, diarrhea, dizziness, and may decrease renal function (4).

 

Long term use of creatine:

Concerns exist regarding the long term risks of the use of creatine supplements since few studies have been conducted long enough in order to evaluate this. Creatine at a dose of 4 grams per day was determined safe in elderly Parkinson’s disease patients with only gastrointestinal complaints, an expected rise in creatinine with breakdown of creatine, normal renal tubular function, and normal glomerular kidney function with monitoring over the duration of 2 years (17).

A study found that healthy adults on a high protein diet and taking creatine at an oral dose of 20 grams per day for 5 days plus 5 grams daily for 12 weeks showed no significant change in markers of renal function including creatinine clearance, urine urea, serum urea, albuminuria, proteinuria, and serum electrolytes between baseline and after 12 weeks as well as when compared to controls (21).

 

Safety of creatine supplementation, kidney function, and case reports:

Yoshizumi WM et al reported that data in 12 relevant articles and case reports, creatine supplementation appears safe when used by healthy adults at the recommended loading (20 gm/day for five days) and maintenance doses (15).

Data and conclusions on the potential harmful effects of oral creatine supplementation in healthy individuals was discussed in a study by HJ Kim, et al. In thus article it was reviewed that healthy subjects supplemented with creatine, liver and kidney function did not appear to change in both young and older populations. Excess creatine ingestion however, is a burden to be eliminated by the kidney and even if there are no obvious health risks associated with oral creatine supplementation it is best to err on the side of caution when supplementing on a chronic basis. The authors advise that high-dose (over 3-5 g/day) creatine supplementation of over 3-5 grams per day should not be used by anyone with pre-existing kidney disease or those with a potential risk for renal dysfunction (diabetes, hypertension, reduced glomerular filtration rate). In conclusion, analysis of kidney function prior to creatine supplementation should be considered for safety reasons but in healthy subjects appears unnecessary. (19)

A healthy 18-year-old man taking the recommended loading (20 g/day for 5 days) and maintenance doses (1 g/day for the next 6 weeks) of creatine monohydrate for bodybuilding purposes presented with a 2-day history of nausea, vomiting and stomach ache. The patient was diagnosed with acute tubular necrosis which can lead to acute kidney failure. Twenty-five days after stopping the creatine supplements, the patient’s blood pressure (120/70 mmHg), serum creatinine (88.4 mmol/L) and proteinuria (82 mg/day) were back to normal, and the patient was discharged from the hospital. (13)

A healthy 24-year-old taking creatine and multiple other supplements for bodybuilding presented with acute kidney injury and proteinuria which is the presence of an excess of serum proteins in the urine indicating kidney stress. After a renal biopsy it was found that he had developed interstitial nephritis. Creatine supplements were discontinued and the patient recovered completely. There have been other reports of renal dysfunction, including acute interstitial nephritis, associated with creatine use. This suggests the safety of creatine supplementation needs to be evaluated further. (14)

A bodybuilder who appeared to be in good health and had no prior tobacco use or history of major medical problems suffered from an ischemic stroke. Prior to the stoke, the bodybuilder took one supplement (dose 2 capsules) containing MaHuang extract (20 mg ephedra alkaloids), 200 mg caffeine, 100 mg L-carnitine, and 200 μg chromium. A second supplement contained 6000 mg creatine monohydrate, 1000 mg taurine,100 mg inosine, and 5 mg coenzyme Q10 per scoop. Additionally, 40–60 mg ephedra alkaloids, 400–600 mg caffeine, and 6000 mg creatine monohydrate were taken daily for 6 weeks prior to having a stroke. (20)

 

Creatine monohydrate and androgens:

A randomized controlled cross-over study was designed to test the resting concentrations of selected androgens (dihydrotestosterone [DHT] and testosterone [T]) after 3 weeks of creatine supplementation in college-aged male rugby players. The total supplementation period was 21 days. A 7-day loading phase with creatine (25 g/day creatine with 25 g/day glucose) or placebo (50 g/day glucose). Followed by 14 days of maintenance (5 g/day creatine with 25 g/day glucose or 30 g/day glucose placebo). Testosterone levels did not change substantially for either the placebo or the creatine phase at any time point. However, DHT levels increased by 56% after 7 days of creatine loading and remained 40% above baseline after 14 days maintenance (p<0.001). The ratio of DHT:T also increased by 36% after 7 days of creatine supplementation and remained elevated by 22% after the maintenance dose (p<0.01). These findings suggest that creatine supplementation increased the rate of conversion of testosterone to DHT. In the medical literature DHT has been associated with hair loss, benign prostate hypertrophy (BPH) and prostate cancer. (16)

 

 

Assessment and Plan: Creatine

• Creatine is available in nutrition stores throughout the country in the form of creatine monohydrate. It has been used in research as an investigational agent in an intravenous form known as creatine phosphate.

 

• Creatine monhydrate dose:
  • Most research reviewed on use of creatine documented that this supplement is safe, well-tolerated and has with minimal side effects in healthy adult men and women as well as in elderly patients at doses of 3-5 mg per day up to 2 years.
  • Most common for healthy adults: Creatine monohydrate, 20 grams per day in 4 divided doses for 5 days followed by a maintenance dose of 2-5 grams per day for 8-12 weeks (3).
  • Highest dose noted in research was 20 grams by mouth daily for 8 weeks (3), which may be unsafe and is not recommended.
  • The longest duration of creatine dosing studied was 4 grams per day by mouth for 2 years by elderly patients (17).
  • In children and adolescents the safety of creatine is not known (15), therefore creatine use is not advised in this group.

 

• Creatine and enhancement of athletic performance:
  • Creatine supplementation improves strength in older men: Men at an average age of 70.4 years old significantly increased lean mass compared to placebo (3.3 kg vs 1.3 kg), higher leg press weight (50.1 kg vs 31.3kg), knee extension endurance (21 reps vs 14 reps), and average power output (26.7 watts vs 18 watts) (1). Additional research on 55-82 year olds by Dalbo, VJ et al concluded that creatine be strongly considered as a safe, inexpensive and effective nutritional intervention to help slow the rate of muscle deterioration with age, particularly when consumed in conjunction with a resistance training regimen (5).
  • Creatine use improves strength in both men and women: A short regimen of only 0.35 grams per kg of fat-free mass for 3 days increased body mass, thigh muscle volume, and improved sprint performance with a greater effect for men than women during the first sprint but in later sprints women experienced a greater effect (2).
  • A meta-analysis of 16 studies showed that creatine groups consistently had higher strength than placebo groups in weight lifting tasks but no enhancement of performance was seen in cycling or endurance activities (3). Other research has confirmed these findings (4).
  • Combining whey and creatine monohydrate appears to increase lean tissue mass better than whey protein alone and better than placebo (6), but it is unknown whether whey protein provides greater benefit than creatine monohydrate alone.

 

• Creatine and bone density: Creatine plus resistance training appeared to increase bone density on dual energy X-ray absorptiometry (Dexa scan) over placebo plus resistance training for 12 weeks. (0.3 grams per kilogram of creatine monohydrate was given for 5 days and then 0.07 grams per kilogram) (7).

 

• Creatine monohydrate and patients on dialysis: A small 12 mg oral dose of creatine monohydrate for 4 weeks resulted in a 60% reduction the frequency of muscle cramps over placebo without major side effects (9).

 

• Creatine and chronic heart failure: 20 g of creatine for 5 days increased the amount of exercise subjects could complete before reaching exhaustion while also lowering serum ammonia and lactate levels with use of creatine but not with placebo (10).

 

• Creatine phosphate in heart surgery: Creatine phosphate given IV perioperatively for coronary bypass surgery appears to show improved heart function (12), reduce ventricular arrhythmias (11,12), and reduce the use of inotropic drugs (12).

 

• Creatine use in Parkinson’s disease: Patients taking creatine did not appear to reduce the loss of dopaminergic neurons but they did not require as much therapy as placebo for Parkinson’s symptoms (17).

 

• Creatine and cognition in older patients: Creatine supplementation by elderly subjects at a dose of 5 grams four times a day for 1 week improved random number generation, forward number recall, spatial recall, and long-term memory tasks over placebo but creatine did not improve backward number recall (18).

 

• Creatine safety concerns, adverse reactions, interactions, and long term use:
  • Creatine safety:
  • Creatine is most likely safe in healthy individuals excluding children and adolescents at doses of 3-5 grams per day and analysis of kidney function prior to creatine supplementation should be considered for safety reasons but in healthy subjects, this appears unnecessary (19).
  • High-dose creatine supplementation of over 3-5 grams per day should not be used by anyone with pre-existing kidney disease or those with a potential risk for renal dysfunction (diabetes, hypertension, reduced glomerular filtration rate). In these patients, creatine should only be considered if kidney function will be evaluated and creatine use will be monitored under a physician’s direction prior to taking.
  • Patients should be advised to report major reactions during use of creatine.
  • Reports have linked creatine to weight gain, cramping, dehydration, diarrhea, dizziness, and may decrease renal function (4).
  • Creatine may be unsafe when combined with other supplements (20).
  • Creatine monohydrate and androgens: Creatine loading for one week plus maintenance dose for 2 weeks did not alter testosterone levels, but dihydrotestosterone (DHT) levels increased by 56% after 7 days of creatine loading and remained 40% above baseline during maintenance which showed that creatine appears to readily convert testosterone to DHT at an increased rate which may be associated with hair loss, benign prostate hypertrophy and prostate cancer (16).
  • Long term use of creatine:
    • Creatine at a dose of 4 grams per day was determined safe in elderly Parkinson’s disease patients with only gastrointestinal complaints, an expected rise in creatinine with breakdown of creatine, normal renal tubular function, and normal glomerular kidney function with monitoring over the duration of 2 years (17).
    • High protein diet plus creatine used by healthy adults at an oral dose of 20 grams per day for 5 days plus 5 grams daily for 12 weeks showed no significant change in markers of renal function including creatinine clearance, urine urea, serum urea, albuminuria, proteinuria, and serum electrolytes between baseline and after 12 weeks compared to controls (21).
  • Case reports
    • A 20-year-old man taking creatine at 20 gm/day for 4 weeks resulted in acute kidney injury (19).
    • An 18-year-old man taking the recommended loading and maintenance doses developed acute tubular necrosis which resolved after 25 days (13).
    • A 24-year-old taking creatine and multiple other supplements for bodybuilding developed acute interstitial nephritis diagnosed by renal biopsy but multiple other supplements may have been the underlying cause (14).
    • A young bodybuilder in good health developed ischemic stroke after taking MaHuang extract (20 mg ephedra alkaloids), 200 mg caffeine, 100 mg L-carnitine, 200 μg chromium, 6000 mg creatine monohydrate, 1000 mg taurine,100 mg inosine, 5 mg coenzyme Q10, and daily use of 40–60 mg ephedra alkaloids, 400–600 mg caffeine, and 6000 mg creatine monohydrate for 6 weeks prior to having the stroke (20).

 

 

References:

1.Chrusch MJ, Chilibeck PD, Chad KE, Davison KS, Burke DG. Creatine supplementation combined with resistance training in older men. Med Sci Sports Exerc. 2001 Dec;33(12):2111-7. http://www.ncbi.nlm.nih.gov/pubmed/11740307

 

2.Ziegenfuss TN, Rogers M, Lowery L, Mullins N, Mendel R, Antonio J, Lemon P. Effect of creatine loading on anaerobic performance and skeletal muscle volume in NCAA Division I athletes. Nutrition. 2002 May;18(5):397-402. http://www.ncbi.nlm.nih.gov/pubmed/11985944

 

3.Dempsey RL, Mazzone MF, Meurer LN. Does oral creatine supplementation improve strength? A meta-analysis. J Fam Pract. 2002 Nov;51(11):945-51. http://www.ncbi.nlm.nih.gov/pubmed/12485548

 

4.Graham AS, Hatton RC. Creatine: a review of efficacy and safety. J Am Pharm Assoc (Wash). 1999 Nov-Dec;39(6):803-10; quiz 875-7. http://www.ncbi.nlm.nih.gov/pubmed/10609446

 

5.Dalbo VJ, Roberts MD, Lockwood CM, Tucker PS, Kreider RB, Kerksick CM. The effects of age on skeletal muscle and the phosphocreatine energy system: can creatine supplementation help older adults. Dyn Med. 2009 Dec 24;8:6. http://www.ncbi.nlm.nih.gov/pubmed/20034396

 

6.Burke DG, Chilibeck PD, Davidson KS, et al. The effect of whey protein supplementation with and without creatine monohydrate combined with resistance training on lean tissue mass and muscle strength. Int J Sport Nutr Exerc Metab. 2001 Sep;11(3):349-64. http://www.ncbi.nlm.nih.gov/pubmed/11591884

 

7.Chilibeck PD, Chrusch MJ, Chad KE, et al. Creatine monohydrate and resistance training increase bone mineral content and density in older men. J Nutr Health Aging. 2005 Sep-Oct;9(5):352-3. http://www.ncbi.nlm.nih.gov/pubmed/16222402/?dopt=Abstract

 

8.Chillibeck, P. D., Chrusch, M. J., Chad, K. E., Shawn Davison, K. and Burke, D. G. Creatine monohydrate and resistance training increase bone mineral content and density in older men. J Nutr Health Aging. 2005 Sep-Oct;9(5), 352-353. http://www.ncbi.nlm.nih.gov/pubmed/16222402

 

9.Chang CT, Wu CH, Yang CW, Huang JY, Wu MS. Creatine monohydrate treatment alleviates muscle cramps associated with haemodialysis. Nephrol Dial Transplant. 2002 Nov;17(11):1978-81. http://www.ncbi.nlm.nih.gov/pubmed/12401856

 

10.Andrews R, Greenhaff P, Curtis S, et al. The effect of dietary creatine supplementation on skeletal muscle metabolism in congestive heart failure. Eur Heart J. 1998 Apr;19(4): 617-622. http://www.ncbi.nlm.nih.gov/pubmed/9597411

 

11.Cerný J, N?mec P, Bucek J, Cerný E, Papousek F, Lojek A. The effect of creatine phosphate in patients after surgery in ischemic heart disease. Czech. Vnitr Lek. 1993 Feb;39(2):153-9. http://www.ncbi.nlm.nih.gov/pubmed/8506662

 

12.Cisowski M, Bochenek A, Kucewicz E, Wnuk-Wojnar AM, Morawski W, Skalski J, Grzybek H. The use of exogenous creatine phosphate for myocardial protection in patients undergoing coronary artery bypass surgery. J Cardiovasc Surg (Torino). 1996 Dec;37(6 Suppl 1):75-80. http://www.ncbi.nlm.nih.gov/pubmed/10064355

 

13.Basturk Taner, Ozagari Aysim and Unsal Abdulkadir. The effects of the recommended dose of creatine monohydrate on kidney function. Clinical Kidney Journal. 2010; 4(1); 23-24. http://ckj.oxfordjournals.org/content/4/1/23.full

 

14.Thorsteinsdottir B, Grande JP, Garovic VD. Acute renal failure in a young weight lifter taking multiple food supplements, including creatine monohydrate. J Ren Nutr. 2006 Oct;16(4):341-5. http://www.ncbi.nlm.nih.gov/pubmed/17046619

 

15.Yoshizumi WM, Tsourounis C. Effects of creatine supplementation on renal function. J Herb Pharmacother. 2004;4(1):1-7. http://www.ncbi.nlm.nih.gov/pubmed/15273072

 

16.van der Merwe J, Brooks NE, Myburgh KH. Three weeks of creatine monohydrate supplementation affects dihydrotestosterone to testosterone ratio in college-aged rugby players. Clin J Sport Med. 2009 Sep;19(5):399 404. http://www.ncbi.nlm.nih.gov/pubmed/19741313

 

17.Bender A, Samtleben W, Elstner M, Klopstock T. Long-term creatine supplementation is safe in aged patients with Parkinson disease. Nutr Res. 2008 Mar;28(3):172-8. http://www.ncbi.nlm.nih.gov/pubmed/19083405

 

18.McMorris T, Mielcarz G, Harris RC, Swain JP, Howard A. Creatine supplementation and cognitive performance in elderly individuals. Neuropsychol Dev Cogn B Aging Neuropsychol Cogn. 2007 Sep;14(5):517-28. http://www.ncbi.nlm.nih.gov/pubmed/17828627

 

19.Kim HJ, Kim CK, Carpentier A, Poortmans JR. Studies on the safety of creatine supplementation. Amino Acids. 2011 May;40(5):1409-18. Epub 2011 Mar 12.

http://www.ncbi.nlm.nih.gov/pubmed/21399917

 

20.Vahedi K, Domigo V, Amarenco P, Bousser MG. Ischaemic stroke in a sportsman who consumed MaHuang extract and creatine monohydrate for body building. J Neurol Neurosurg Psychiatry. 2000 Jan;68(1):112-3. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1760579/pdf/v068p00112.pdf

 

21.Lugaresi R, Leme M, de Salles Painelli V, Murai IH, Roschel H, Sapienza MT, Lancha Junior AH, Gualano B. Does long-term creatine supplementation impair kidney function in resistance-trained individuals consuming a high-protein diet? J Int Soc Sports Nutr. 2013 May 16;10(1):26. http://www.ncbi.nlm.nih.gov/pubmed/23680457